1. Field of the Invention
This invention relates generally to therapies for treating autoimmune diseases and, more particularly, to administering primary agents being estrogens or estrogen receptor active agents for the treatment of cell mediated diseases. In combination, secondary agents which effect the immune system are also administered. Finally, treatment kits are provided containing at least one primary agent and at least one secondary agent for treating a patient presenting with symptomology of an autoimmune disease.
More specifically, the present invention may comprise a combination of a pregnancy hormone (such as estriol), combined with a gestagen (such as levonorgestrel or norethindrone) for treating autoimmune diseases. The combination may be useful at least for the continuous treatment and prevention of relapses in patients having an autoimmune disease, such as multiple sclerosis, obviating the need for pregnancy hormone therapy holidays for menstruation that may be associated with higher rates of relapse of disease during such holiday.
2. General Background and State of the Art
There is a distinct female preponderance of autoimmune diseases during the reproductive ages including multiple sclerosis (MS), rheumatoid arthritis (RA), uveitis, myesthenia gravis (MG), Sjogren's syndrome, Hashimoto's thyroiditis, psoriasis, and lupus.
For example, MS is a chronic, and often debilitating disease affecting the central nervous system (brain and spinal cord). MS affects more than 1 million people worldwide and is the most common neurological disease among young adults, particularly woman. The exact cause of MS is still unknown. MS attacks the nervous system resulting in myelin sheaths surrounding neuronal axons to be destroyed. This demyelinization can cause weakness, impaired vision, loss of balance, and poor muscle coordination. MS can have different patterns, sometimes leaving patients relatively well after episodes of acute worsening, sometimes leading to progressive disability that persists after episodes of worsening. In the worst cases the disease can lead to paralysis or blindness.
Steroid hormones or sex-linked gene inheritance may be responsible for the enhanced susceptibility of women to these autoimmune diseases. A role for steroid hormones in susceptibility to autoimmune disease is supported by observations of alternations in disease symptomatology, with alterations in sex hormone levels such as during pregnancy. For example, women with MS, RA and psoriasis have been reported to experience remission of symptoms during late gestation. Particularly, MS patients have been reported to show a decrease in relapse rate in pregnancy.
Normally, cell-mediated immunity is mediated by T helper cell (Th1) secretion of interferon gamma (IFN-γ) and tumor necrosis factor beta (TNF-β). In contrast, humoral immunity is mediated by another group of T helper cells (Th2) secreting interleukin (IL)-10, IL-4, IL-5 and IL-6. A systemic shift toward humoral immunity (or Th2-mediated immunity) has been noted during pregnancy. During pregnancy, cell-mediated immunity is decreased and humoral-mediated immunity is increased thereby promoting fetal survival. Thus, this systemic shift in the immune system may explain why cell-mediated diseases, including MS, RA and psoriasis have been reported to improve during pregnancy.
Although a shift toward humoral-mediated immunity has been demonstrated during human pregnancy, mechanisms which induce this shift remain unclear. One possibility is local production of Th2 (or humoral mediated) cytokines by the placenta. Another possibility is the production of Th2 cytokines by immune cells, consequent to changed levels of steroid hormones during pregnancy. Consistent with the latter possibility, in vitro studies have demonstrated the ability of the steroid progesterone to increase IL-4 production and the ability of the steroid 17β-estradiol to increase IL-10 production during T-lymphocyte responses. However, it remains unclear what cellular mechanisms are involved in regulating in vivo amelioration of autoimmune symptomology.
Examples of potential candidates which effect may effect MS during pregnancy include: Sex hormones (estrogens, progesterone), cortisol, vitamin D, alpha-fetoprotein, human chorionic gonadotropin and pregnancy specific glycoproteins.
Further, some studies have suggested that a unique pregnancy factor termed “early pregnancy factor” is responsible for improved progression of cell-mediated autoimmune diseases during pregnancy. Other studies have suggested a role for microchimerism. Still others suggest a role for local factors such as TGFβ or estriol (E3) which is known to be produced by the placenta during pregnancy. Of note, estriol is at its highest serum levels in the third trimester of pregnancy. However, estriol's role in ameliorating symptoms of autoimmune diseases in humans is unclear.
Studies in laboratory animals have established that experimental autoimmune encephalomyelitis (EAE) and other Th1 (cell-mediated) autoimmune diseases in mice improve during pregnancy.
Specifically, treatment with late pregnancy levels of estriol or supraphysiological doses of estradiol (5 times pregnancy levels) were shown to delay the onset of clinical EAE after disease was experimentally induced by immunization of mice (Jansson, et al., 1994). However, there was no investigation as to how estrogens delayed the day of onset of disease, nor as to whether disease severity was effected in these animals once symptomology occurred.
In another study, it was shown that EAE disease severity could be reduced by treatment with estriol, either before or after disease onset. Treatment of EAE mice with 90 day release pellets of 5 milligrams or 15 milligrams of estriol was shown not only to decrease disease severity but also to enhance autoantigen specific humoral-immunity, increase production of the Th2 cytokine IL-10 and reduced inflammation and demyelination in EAE mice. Importantly, these changes in the disease were induced by a dose (5 mg) which was shown to yield estriol levels in serum that were similar to those which occur during late pregnancy (Kim, et al., Neurology, 50 (4 Supp. 4):A242-245, April 1998, FASEB Journal 12(4):A616, March 1998 and Neurology 52(6):1230-1238, April 1999; herein incorporated by reference). Thus, these results suggested that steroid hormones, and estriol in particular, may be involved in the amelioration of autoimmune reactions in the EAE animal model.
Other groups later demonstrated that estrogen potentiated the effects of treatment with TCR proteins to reduce autoimmune reactions in EAE mice. Offner, et al., FASEB Journal 14(6):A1246, April 2000; Int. Journal of Mol. Medicine 6 (Supp. 1): S8, October 2000 and Journal of Clin. Invest. 105(10):1465-1472, May 2000). Further, it was shown in animal studies that estrogen suppressed the onset EAE in mice (Ito, et al., Journal of Immunology, 167(1): 452-52, 2001) and that presumed diestrus levels of estrogens reduced some manifestations of active EAE in mice. (Bebo, et al., Journal of Immunology 166(3): 2080-9, 2001.)
However, the etiology and disease progression of EAE and MS are not identical, thus it is unclear that estrogens alone would be effective in ameliorating autoimmune responses in human patients. Indeed, not only is it unknown whether pregnancy doses of estrogens might be protective in humans with autoimmune disease, it is unclear even in mice whether low doses of estrogens are protective. For example, it has been reported by some that ovariectomy of female mice makes EAE disease worse (Matejuk, et al., 2001), while others have found that ovariectomy had no effect on disease severity (Kim, et al., 2001; Voskuhl and Palaszynski, 2001a; Voskuhl and Palaszynski, 2001b). Thus, it is controversial whether low levels of estrogens, as they exist during the menstrual cycle, are protective even in mice.
Data from human studies to date have shown no clear benefit of hormones in treating any autoimmune disease. In humans, administration of available hormone therapies (including HRTs and OCPs) containing a mixture of sex hormones cause some autoimmune diseases to improve while others worsen.
For example, there has been no conclusive evidence that women are protected from or have a decrease in symptomology or relapse rates due to sex steroids. One study noted that past use of oral contraceptives in healthy women had no effect on subsequent risk to develop MS (Hernan, et al., 2000). Further, another study found that the incidence rates for MS in current users were not decreased as compared to never-users (Thorogood and Hannaford, 1998). Thus, low doses of estrogens in oral contraceptives are not of sufficient type or dose to ameliorate the immunopathogenesis of MS even temporarily during intercurrent use. At best, in one study, patients had the subjective impression that pre-existing MS symptoms (as opposed to relapse rates) worsen during the premenstrual period and that the use of oral contraceptives may have decreased this worsening (Zorgdrager and De Keyser, 1997). Importantly, the lack of reports of an effect of oral contraceptive therapy on MS relapses is in marked contrast to what has been observed during pregnancy.
In contrast, it has been shown that women had a lower risk of developing MS during pregnancy compared to non-pregnant states (Runmarker and Andersen, 1995). Due to the numerous changes that occur during pregnancy, hormonal and nonhormonal (as listed above), the etiology of the beneficial effect of pregnancy may or may not be related to sex steroid fluctuations. It has also been reported for decades that pregnancy decreases MS relapses (Abramsky, 1994; Birk, et al., 1990; Birk, et al., 1998; Damek and Shuster, 1997; Runmarker and Andersen, 1995; Confavreux, et al., 1998). These studies have shown that the latter part of pregnancy is associated with a significant reduction in relapses, while there is a rebound increase in relapses post partum. In contrast, the absence of such an effect on relapses during OCP or HRT indicate that low level sex steroids are not adequate to treat these symptoms.
Further, women having rheumatoid arthritis that were treated with HRT did not show significant improvement in their symptomology. (DaSilva and Hall, Baillieres Clinical Rheumatology 1992, 6:196-219; Bijlsma, et al., Journal of Repro. Imm. 28(3-4):231-4, 1992; Hall, et al., Annals of the Rheumatic Diseases, 53(2): 112-6, 1994.)
Thus, the low doses of hormones found naturally during the menstrual cycle or in ORT and HRT have not been shown to be effective at ameliorating the symptomology of autoimmune diseases. This is in spite of the observation that women having MS have a decreased relapse rate during late pregnancy. Thus, a challenge has been to identify a hormone and a treatment dose that is therapeutic in treating particular autoimmune diseases, while minimizing undesirable side effects. Obviously, the dose and method of administration of steroids in humans differs from steroid treatment in laboratory animals due to toxic effects of prolonged exposure by patients to steroid hormones. In particular, there are clinical concerns of inducing breast or endometrial cancers in women requiring long term exposure to steroid hormones.
Although not available in the United States, the pregnancy hormone estriol has been recently prescribed in Europe and Asia largely as an HRT for postmenopausal women. On the other hand, hormonal contraceptives have been widely prescribed for premenopausal and perimenopausal women since the 1960's. Since that time, a number of hormonal components have been investigated as to their suitability for administration. A fundamental subdivision into combination and sequential contraceptive products is possible.
For example, if the desired cycle time is 28 days (in the case of the known combination products) administration takes place over 21 days in a constant or varying absolute and/or relative dosage of a combination of an estrogen and a gestagen, in which the estrogen product can, for example, be natural estrogen or synthetic ethinyl estradiol. The taking of the 21 daily units is followed by a seven-day interval where there is a withdrawal bleeding simulating natural menstruation.
In the known sequential products, for a desired cycle time of 28 days, administration takes place for 7 days of a pure estrogen product and then for 15 days of a combination of an estrogen product and a gestagen product, followed by a taking-free period of, for example, 6 days when withdrawal bleeding occurs. It is known to bridge the taking-intervals of combination and sequential products to administer placebos. However, it has been assumed that during the roughly one-week placebo interval no hormones should be administered, in order to ensure a reliable withdrawal bleeding.
Only in the case of substitution products in the menopause of older women have hormones been administered continuously throughout the cycle, for example, in the sequence 10 days estrogen product, 11 days combination of estrogen and gestagen product, 7 days estrogen product in a particularly low dosage.
German Patent No. 43 08 406 discloses a combination contraceptive product for premenopausal women, which comprises one or more stages. At least one stage contains the combination of three components, namely a biogenous estrogen, a synthetic estrogen and a gestagen and the further stages in each case comprise a placebo or a biogenous or synthetic gestagen, or a biogenous or synthetic estrogen, or a combination of two components, namely a biogenous estrogen, a synthetic estrogen and a gestagen or a combination of synthetic estrogen and a gestagen.
U.S. patent application Ser. No. 10/867,954 filed by Hesch published Dec. 2, 2004 and assigned to Wyeth Pharmaceuticals, Inc. describes estrogens and gestagens as combination products for continuous hormonal contraception in premenopausal women, but does not describe their use for autoimmune disease. Furthermore, although estriol is mentioned as an estrogen in this patent application, the preferred embodiment contemplates the use estradiol, which is not pregnancy hormone, and utility of which has been clinically proven to be ineffective for the treatment of autoimmune diseases (such as MS).
The description above makes it clear that in the stage concept there is typically a change of state over the period of time. Such a state change can take place in that the composition of the phases forming the stage is modified with respect to the components used and in that only the concentrations of the components used in the phases forming the stage undergo changes.
Consequently, there are no hormone combinations identified for safe and effective use to delay and/or treat autoimmune diseases, and for potential continuous therapies.